Antibiotics against most pathogenic bacteria have been developed, but problems may often occur during the use thereof.
Many antibiotics, for instance, exhibit a low solubility in an aqueous medium, i.e. at their strongest dose they are only poorly or not at all soluble at 37° C. in aqueous media with a pH of 1 to 7.5, in particular in corresponding standard buffer solutions of ≦250 ml. It is here particularly unfavourable if this low solubility occurs at pH values which correspond to the physiological pH values in the environment of the small intestine. The antibiotic should in fact be available as fast as possible in the small intestine, since it is there that absorption of the antibiotic mainly takes place. Many antibiotics are therefore preferably administered as a solution or suspension in order to achieve the highest possible bioavailability.
Furthermore, numerous antibiotics often also have a particularly bitter flavor which means that, despite being flavored, such solutions or suspensions are taken only unwillingly by patients, in particular by children.
As a consequence, during treatment with antibiotics, which usually lasts for several days, it becomes ever more difficult to motivate the patient to complete the course of treatment. The unwillingness of patients to take the medicine thus often results in premature termination of treatment, which may have particularly harmful effects with antibiotics, such as development of resistance.
Another disadvantage of these administration forms is that the antibiotics are conventionally marketed as powders for suspension in order to facilitate production, transport and storage in comparison to finished solutions or suspensions. The dry substance is converted into a suspension just before it is first administered. However, the prepared suspension must often be kept in the refrigerator and, as explained above, taken over a period of several days.
This means further unpleasantness for the patient since the prepared suspension may undergo a progressive deterioration in flavor over the course of storage or the suspended fractions may agglomerate when left to stand for an extended period, so entailing redispersion and thus impairing dose accuracy. Moreover, cooling of the suspension, which is often necessary, also impairs unproblematic taking of the antibiotic.
In order to avoid these disadvantages, effervescent tablets may also be used to prepare a suspension, one tablet conventionally corresponding to an individual dose. Such freshly prepared solutions or suspensions nevertheless have a bitter flavor for the patient.
Taking dry antibiotics in the form of granules, pellets or microtablets, packaged in sachets, which must conventionally be swallowed with the assistance of a liquid is also problematic. Children in particular have problems with taking such dosage forms. With dosage forms which have not been flavor-neutralised, it may happen that just some of the antibiotic is released in the mouth within a short time and causes an unpleasant flavor.
When taking dry preparations in this manner, it is also not ensured that the entire necessary dose is swallowed or so quickly swallowed that any only temporary flavor-masking effect is sufficiently effective.
In order to avoid such problems, dosage forms have been developed in which the antibiotic is arranged in a drinking straw preferably in multiparticulate form, from which it is taken by the patient with the assistance of a conveying liquid. With this type of taking, it is particularly advantageous for the multiparticulate dosage form to assume the form of rounded, spherical pellets with a particle size of no more than 800 μm, because such particles are effortlessly conveyed by the patient's sucking up the conveying liquid and may thus be taken in their entirety.
Care must, however, be taken to ensure, preferably taking account of swallowing behaviour of children, that the volume and mass of the particles is kept as small as possible, which entails an elevated active ingredient loading of the multiparticulate dosage forms. As is known, an elevated active ingredient loading is in particular achieved with extruded pellets, which moreover enable the desired smooth, preferably spherical shape. One disadvantage of this type of dosage form, however, is that, due to the auxiliary substances necessarily used in the conventional manufacturing method, the dosage forms usually have a very compact structure and therefore do not disintegrate in water or an aqueous medium or at most do so very slowly or only in part. As is known, this may result in delayed release of the active ingredient, in particular in the case of an antibiotic which is sparingly wettable with aqueous media and/or sparingly soluble in aqueous media. This applies particularly if said sparing wettability or sparing solubility occurs at the physiological pH values in the environment of the upper small intestine, as described above. As a consequence, release of the antibiotic may then not occur to a considerable extent until in the lower part of the intestine.
However, with many antibiotics, this prevents adequate bioavailability, as these are mainly absorbed in the upper portion of the small intestine. This low dissolution rate of the dosage form and thus the delayed release of the active ingredient is in particular observed when using known spheronising agents, such as microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, which, while indeed giving rise to pellets in the desired, namely spherical, shape and with a smooth surface and to a narrower particle size distribution, bring about delayed, diffusion-controlled release of the active ingredient, especially if the antibiotic is sparingly soluble in aqueous media and/or sparingly wettable.
This is also observed to a still greater extent with the extruded pellets produced with the assistance of the stated spheronising agents after dissolution of a coating which is present and may preferably be resistant to saliva and/or gastric juice and preferably performs a flavor-neutralisation function. Even after pH-dependent dissolution of the coating, despite preswelling or the addition of disintegrants, the pellets disintegrate very slowly or not at all, so delaying release of the antibiotic and limiting bioavailability.